Vps11-KO Mouse

Vps11, the core subunit of the CORVET and HOPS complexes, is crucial for endosomal fusion. It also functions as an E3 ubiquitin ligase and is involved in regulating autophagy, making it important for multiple biological processes [1,3]. Vps11 participates in signal transduction pathways, such as Wnt, estrogen receptor α (ERα), and NFκB, through ubiquitination [1].

A novel homozygous VPS11 variant has been associated with adult-onset generalized dystonia. Functional studies on mutated fibroblasts showed lysosomal and autophagic abnormalities, which improved upon overexpression of wild-type Vps11 protein [2]. In zebrafish vps11 mutant lines, loss of Vps11 function led to progressive visual and sensorimotor abnormalities, mimicking symptoms of genetic leukoencephalopathy [4]. Also, knockdown of Vps11 in relevant studies increased retrograde transport of toxins like Shiga toxin and ricin, and restored reduced glycolipid levels [5].

In conclusion, Vps11 is essential for endosomal fusion, autophagy regulation, and signal transduction. Model-based research, especially in zebrafish mutants and fibroblast functional studies, has revealed its role in diseases like generalized dystonia and genetic leukoencephalopathy. Understanding Vps11's functions can potentially provide insights into treating such neurological disorders.

References:

1. Segala, Gregory, Bennesch, Marcela A, Ghahhari, Nastaran Mohammadi, Maeda, Robert K, Picard, Didier. 2019. Vps11 and Vps18 of Vps-C membrane traffic complexes are E3 ubiquitin ligases and fine-tune signalling. In Nature communications, 10, 1833. doi:10.1038/s41467-019-09800-y. https://pubmed.ncbi.nlm.nih.gov/31015428/

2. Monfrini, Edoardo, Cogiamanian, Filippo, Salani, Sabrina, Aureli, Massimo, Di Fonzo, Alessio. 2021. A Novel Homozygous VPS11 Variant May Cause Generalized Dystonia. In Annals of neurology, 89, 834-839. doi:10.1002/ana.26021. https://pubmed.ncbi.nlm.nih.gov/33452836/

3. Luo, Dan, Wu, Jialing, Liu, Yinyin, Liu, Ting, Pan, Jianhua. 2022. Overexpression of VPS11 antagonizes the promoting effect of miR-542-3p on Mycobacterium tuberculosis survival in macrophages by regulating autophagy. In Microbial pathogenesis, 169, 105609. doi:10.1016/j.micpath.2022.105609. https://pubmed.ncbi.nlm.nih.gov/35662671/

4. Banerjee, Shreya, Ranspach, Lillian E, Luo, Xixia, Perkins, Brian D, Thummel, Ryan. 2022. Vision and sensorimotor defects associated with loss of Vps11 function in a zebrafish model of genetic leukoencephalopathy. In Scientific reports, 12, 3511. doi:10.1038/s41598-022-07448-1. https://pubmed.ncbi.nlm.nih.gov/35241734/

5. Kvalvaag, Audun Sverre, Pust, Sascha, Sandvig, Kirsten. 2014. Vps11, a subunit of the tethering complexes HOPS and CORVET, is involved in regulation of glycolipid degradation and retrograde toxin transport. In Communicative & integrative biology, 7, e28129. doi:10.4161/cib.28129. https://pubmed.ncbi.nlm.nih.gov/24778763/